Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression
Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression
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DOI：
10.3892/ijo_00000191
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发表时间：
2009-03-01
影响因子：
5.2
通讯作者：
Kumon, Hiromi
中科院分区：
文献类型：
--
作者：
Watanabe, Masami;Kashiwakura, Yuji;Kumon, Hiromi
据报道，REIC/Dkk-3基因是一种肿瘤抑制因子，其表达在多种癌细胞类型中显著下调。这种蛋白是分泌性的，但其生理功能尚不清楚。本研究证实重组REIC/Dkk-3蛋白诱导人CD14（+）单核细胞分化为一种新的细胞类型（MoREIC/Dkx-3）。MoREIC/ ddk -3类似于IL-4和GM-CSF产生的未成熟树突状细胞。这两种细胞群表现出相似的CD11c（+）、CD40（+）、CD86（+）和HLA-DR+细胞比例和内吞能力，但MoREIC/Dkk-3对CD1a抗原呈阴性。对信号转导和转录激活因子（STAT）通路的分析表明，REIC/Dkk-3诱导STAT 1和STAT 3的磷酸化。此外，瘤内给药REIC/Dkk-3蛋白显著抑制肿瘤生长，CD11c（+）和CD8(+)（分别为树突状细胞和杀伤T细胞标记物）细胞积累，增强脾细胞的抗癌细胞溶解活性。这些数据表明REIC/Dkk-3蛋白在单核细胞分化中的细胞因子样作用可能被用于治疗。
The REIC/Dkk-3 gene has been reported to be a tumor suppressor and the expression is significantly down-regulated in a broad range of cancer cell types. The protein is secretory, but the physiological function remains unclear. This study demonstrated that recombinant REIC/Dkk-3 protein induced the differentiation of human CD14(+) monocytes into a novel cell type (MoREIC/Dkx-3). MoREIC/Dkk-3 resembles immature dendritic cells generated with IL-4 and GM-CSF. Both these cell populations exhibit similar proportions of CD11c(+), CD40(+), CD86(+) and HLA-DR+ cells and endocytic capacity, but MoREIC/Dkk-3 is negative for CD1a antigen. An analysis of the signal transducers and activators of transcription (STAT) pathways revealed that REIC/Dkk-3 induces phosphorylation of STAT 1 and STAT 3. Furthermore, intratumoral administration of REIC/Dkk-3 protein significantly suppressed tumor growth with CD11c(+) and CD8(+) (dendritic and killer T cell marker, respectively) cell accumulation and enhanced anticancer cytolytic activity of splenocytes. These data indicated a cytokine-like role of REIC/Dkk-3 protein in monocyte differentiation that might be exploited therapeutically.